imprint:
[Erscheinungsort nicht ermittelbar]: [Verlag nicht ermittelbar], 2022
Language:
English
Origination:
University thesis:
Dissertation, 2022
Footnote:
Description:
Cardiovascular disease (CVD) is the leading cause of death worldwide. During disease progression, the heart undergoes changes in its size, shape, structure and function referred to as cardiac remodeling. These changes can contribute to both the pathological progression of the disease and the activation of endogenous self-repair mechanisms to overcome the injury (chapter 1, introduction). In this thesis, we made use of different animal and cell culture models to study various aspects of cardiac remodeling, owing for a better molecular understanding of disease mechanisms and for identifying potential targets for therapy. In part I, we utilized different sequencing technologies to identify genes which can beneficially regulate the function of cardiomyocytes following ischemic injury. We found that increased activity of transcription factor ZEB2 is cardioprotective. Gain- and loss-of-function mouse models showed that in response to ischemia, cardiomyocytes express high levels of ZEB2, which induces a paracrine signaling cascade to endothelial cells, thereby promoting cardiac angiogenesis (chapter 2). We further identified the function of ZEB2 as a central regulator of calcium homeostasis components affecting cardiac contractility and function (chapter 3). In part II, we studied cellular and molecular aspects contributing to the pathological remodeling processes taking place in patients with arrhythmogenic cardiomyopathy (ACM). ACM is a genetic disease characterized by lethal ventricular arrhythmias and myocardial replacement with fibro-fatty tissue which further exacerbates cardiac dysfunction. Using human induced pluripotent stem cell (hiPSC)-derived cardiac cultures and single cell sequencing transcriptomics, we showed that epicardial cell differentiation drives fibro-fatty remodeling in ACM, and that this process is mediated through transcription factor TFAP2A (chapter 4). We further performed a literature review of other studies investigating fibro-fatty remodeling processes in ACM and how they relate to our ...